Aminopeptidase N: the glucocorticoid gateway linking chronic stress to ferroptosis resistance in liver cancer

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Abstract

Chronic stress triggers a range of physiological responses that could dysregulate the immune system and metabolic processes, thereby increasing susceptibility to various diseases. In this issue of the JCI, Wu et al. identified a metabolic bridge between chronic stress and liver cancer progression. Chronic stress–induced glucocorticoids promoted aminopeptidase N (ANPEP) expression and subsequent reprogramming of amino acid metabolism, leading to increased liver cancer growth and metastasis. ANPEP facilitated stabilization of the cystine-glutamate transporter system Xc– and increased l-cystine influx, thereby enhancing cellular antioxidant capacity to prevent ferroptosis. Silencing ANPEP in combination with sorafenib treatment showed a synergistic inhibitory effect on liver cancer progression. These findings uncover ANPEP as a valuable target for therapeutic interventions to treat patients with liver cancer experiencing chronic stress.

Authors

Maowu Luo, Weibo Luo